OBJECTIVE To observe the effect of moxibustion on the expression of phosphorylated calcium/calmodulin-dependent protein kinase Ⅱα(pCaMKⅡα) and neuronal nuclei (NeuN) and the ability of learning and memory in the neonatal mice model of hypoxic-ischemia encephalopathy(HIE), so as to explore its mechanism underlying improvement of learning and memory. METHODS ICR mice (aged 7 days) were randomly divided into sham operation, model and moxibustion groups. HIE model was induced by ligation of the right common carotid artery combined with hypoxia in a closed transparent chamber. Mice in the moxibustion group were treated with gentle moxibustion at "Dazhui"(GV14) for 35 min，once daily for 3 consecutive days. The pathological changes of brain tissues were observed with the naked eyes and under microscope after H.E. staining, respectively. The expressions of pCaMKⅡα and NeuN in the ischemic penumbra were examined by immunofluorescent staining, and the learning and memory ablility was tested with Morris maze. RESULTS No infarcts were found in the brain tissue of the mice in the sham operation group. Compared with the sham operation group, mice in the model group had infarcts and the expression of pCaMKⅡα and NeuN in the ischemic penumbra was significantly reduced (P<0.01), and the latency to find a platform was significantly prolonged in Morris maze test (P<0.01). After moxibustion, in comparison with the model group showed that, small areas of infarction were seen in the right hemisphere of the moxibustion group, and the expressions of pCaMKⅡα, NeuN increased significantly (P<0.01), and the latency to find a platform was significantly shortened (P<0.01). CONCLUSIONS Moxibustion can improve the ability of learning and memory in the neonatal mice with HIE, which might be related to alleviating brain injury and increasing the expression of pCaMKⅡα in neurons of ischemic brain tissues.